This research is directed in two areas: studies of damage to critical target genes in environmentally-associated cancers and studies of genetic susceptibility and gene-environment interaction in disease risk. The research on critical target genes tests the hypothesis that environmental exposures produce specific patterns of gene mutation in human tumors. The research on genetic susceptibility tests the hypothesis that commonly inherited allelic variants of certain genes, in conjunction with environmental exposures, affect a persons risk of developing disease. In work on critical target gene damage we have extended our work on uranium miner lung tumors in a paper in press, showing that unlike squamous and small cell tumors which frequently carry a unique mutation at codon 249 of the p53 gene, adenocarcinomas do not carry such a mutation. In a submitted publication we have shown that bladder tumors from arylamine- exposed workers do not differ in their pattern of p53 mutation compared to smoking-associated bladder tumors. Finally, in two papers currently in press, we have shown that there are frequent homozygous deletions, but not point mutations in the putative tumor suppressor genes p15 and p16 on chromosome 9p21 in both lung and bladder cancers. In work on genetic susceptibility we have shown that a common polymorphism in the vitamin D receptor gene leads to a two fold increased risk of prostate cancer (paper submitted). Preliminary results for breast cancer appear to show no association with this polymorphism. In a paper in press we have shown that the metabolism genes GSTM1 and NAT2 do not affect risk of miscarriage And finally, in a submitted manuscript we have tested a previously reported association between a polymorphism in the tumor suppressor gene p53 and ovarian cancer risk. We found no association between this polymorphism and risk of either ovarian cancer or of bladder cancer. We are currently exploring the pattern of mutations in asbestos- associated primary lung tumors and extending our work on p53 mutations in radiation-associated tumors.